Earlier this year the FDA approved telaprevir (Incivek) from Vertex Pharmaceuticals and boceprevir (Victrelis) from Merck for the treatment of hepatitis C. Both agents are protease inhibitors and represent the first approvals of direct acting antivirals for hepatitis C. Direct acting antivirals are a broad class of agents that act to block the growth of viruses by directly disrupting essential viral functions. The benefit of these drugs for hepatitis C follows the dramatic success of this class over the last 15 years in HIV. Now the future advances of direct acting antiviral therapy for hepatitis C is expected to follow a central theme of their use in HIV: that combination of multiple antivirals in a single treatment regimen will provide greater benefit than use of any one antiviral drug alone.

The new protease inhibitors were approved for use only in combination with two previously approved agents, pegylated interferon and ribavirin. The addition of either protease inhibitor increased clinical cure rates, known formally as sustained viral response (SVR) rates, by 30 to 40 percentage points over control groups receiving the standard pegylated interferon and ribavirin alone. As dramatic as these improvements are, there is a good chance for even more dramatic improvements if all-oral regimens, assembled by combining multiple direct acting antivirals, are able to maintain high cure rates while eliminating injectable interferon and its associated flu-like side effects that patients have long sought to avoid.

Next in the development queue are three agents that entered Phase III development this year, including two additional protease inhibitors (TMC435 from Johnson & Johnson’s Tibotec unit and BI201335 from Boehringer Ingelheim) and a cyclophilin inhibitor that disrupts a host function required for viral replication (alisporivir from Novartis). All three Phase III programs are exploring a modality similar to the approved agents, i.e. addition of a single new agent to the standard pegylated interferon/ribavirin. The ongoing Phase III programs will hope to demonstrate one or more advantage over the recently approved agents, potentially including better tolerability, further increases in cure rates, shorter duration of therapy and/or an increased proportion of patients successfully treated with shortened therapy. While such improvements may well be achieved, they may become less important or even irrelevant if the rapidly expanding number of direct acting antiviral combination trials leads to identification of new regimens that surpass all regimens that are based on a single antiviral drug added to the old standard regimen.

Investigation of direct acting antiviral combination regimens has exploded in the last 12 months. This advance has become possible because of the diversity of antiviral mechanisms distinct from protease inhibitors that are now represented in the pipeline of hepatitis C drugs in Phase II development across the industry. Diverse mechanisms are important because they typically provide distinct resistance profiles, and antiviral combinations are being assembled using new compounds with non-overlapping resistance profiles to provide a greater barrier to the development of antiviral resistance. Additional factors that are considered important in assembling optimal combinations include the safety and tolerability profile of each agent, compatible pharmacokinetic profiles and a low potential for unfavorable drug-drug interactions. The more extensively characterized each individual antiviral drug is, the lower the risk of … Next Page »

Comments (16) | Reprints | Share:          

Combination therapy has been a central component of treatment for certain viral diseases for more than 15 years. The benefits of combination therapy can arise from activation of multiple host pathways, suppression of mutational variants that can lead to viral escape, or perhaps both.

In HIV, the benefit of combination therapy is due to suppression of viral resistance, which is the result of using multiple agents acting at distinct sites within the virus life cycle. In hepatitis C (which I’ll abbreviate as HCV) the addition of ribavirin to interferon turned what was primarily an on-treatment lowering of viral titers into the first significant rate of viral clearance that persisted even after therapy was stopped. This sustained virological response, known as SVR, has become the primary measurement of clinical benefit in HCV. The mechanism underlying the dramatic effect of combining ribavirin with interferon is not clear. The benefit could be due to a pharmacologic interaction between pathways activated by interferon and pathways activated by ribavirin, or it may be the result of a modest ribavirin antiviral effect added to an “antiviral state” induced by interferon.

Just this year, companies in the HCV field began exploring the use of direct antiviral combinations. It is hoped that by appropriately choosing complementary targets, benefits of combination similar to what was seen in HIV may soon be seen in HCV therapy. Whether or not the combination of direct antivirals will permit the elimination of interferon and/or ribavirin remains unknown at this time, and is perhaps the most highly anticipated answer in the HCV field today.

Combinations of antivirals today

Three companies have moved into the clinical stage of exploring direct antiviral combinations for HCV.

Roche is most advanced in combination studies of direct antivirals with its INFORM-1 study. In this study, HCV patients were treated for 14 days with various dose levels of two drug candidates that inhibit different parts of the virus life cycle. These drug candidates are RG7128, a nucleoside polymerase inhibitor licensed from Pharmasset, and RG7227, a protease inhibitor licensed from Intermune. Data from the first several dosing cohorts was disclosed this past April at the annual meeting of the European Association for the Study of the Liver. Additional data, including responses at higher doses and in patients who previously failed interferon/ribavirin, will is being reported at the annual meeting of the American Association for the Study of Liver Diseases conference in Boston.

The INFORM-1 study clearly shows that two antiviral agents can act in concert to produce a greater antiviral effect over 14 days than either agent produced alone. At the same time, critical questions remain for longer studies — Can direct antivirals alone retain viral titers at undetectable levels over longer periods of treatment? Even more important, will a state of virus negativity elicited by a direct antiviral combination afford the same rate of SVR once therapy is stopped as when virus negativity is induced by the interferon/ribavirin combination? Is there anything special … Next Page »

Comments | Reprints | Share: